The NMDA receptor (NMDAR) antagonist, ketamine, is currently in experimental use for the treatment of severe, intractable depression. Emerging clinical data indicate that intranasal ketamine administration can produce relief within minutes (5~40min), with fewer cognitive side effects than systemic ketamine injections. The proposed research will use a non-human primate paradigm to study the cellular and circuit mechanisms underlying the effects of intranasal vs. injected ketamine administration in prefrontal cortical (PFC) circuits immediately relevant to depression and cognition. We have observed persistent neuronal activity in medial PFC related to aversive events in a decision-making task, which may contribute to negative affective states and be abnormally heightened in depression. We will test the hypothesis that ketamine rapidly erodes the persistent representations of loss and punishment generated by medial prefrontal neurons, similar to ketamine's ability to erode persistent representations of visual space by dorsolateral prefrontal cortical (dlPFC) neurons. We hypothesize that the disruption of neural circuits representing loss may underlie the ultra-rapid effects of intranasal ketamine in patients (within minutes), while spinogenesis in higher order PFC regions may contribute to the more sustained anti-depressant actions (hours to days). As intranasal inhalation delivers drug directly to the brain through the holes in the cribiform plate, we further hypothesize that the medial PFC regions in the direct trajectory of intranasal ketamine may be more affected than the dlPFC neurons that are more distant. Such data would help to explain why intranasal administration has a more rapid onset with fewer cognitive side effects than ketamine injections. Aim 1 will compare the effects of intranasal vs. intramuscular administration of sub-anesthetic doses of ketamine on performance of the decision-making vs. spatial working memory tasks. We predict that ketamine will attenuate the effects of previous punishment on decision-making, allowing a more resilient behavioral response, and that intranasal administration will preferentially influence this behavior, while IM injections will have more global effects on performance in both tasks. Aim 2 will compare the effects of intranasal vs. intramuscular administration of ketamine on persistent neuronal firing in medial PFC regions relevant to depression (BA24, BA25 and dmPFC) compared to the dlPFC. We predict that ketamine will rapidly erode persistent representations of loss in medial PFC areas. We further hypothesize that intranasal administration will have more targeted effect on medial PFC neurons, while IM ketamine will alter neuronal firing in both medial and lateral PFC areas. Finally, Aim 3 will test whether the effects of ketamine are mediated by local actions in the medial PFC using iontophoretic application of ketamine and other more selective NMDAR NR2A vs. NR2B antagonists directly onto medial PFC neurons, similar to previous experiments in the dlPFC. The results from these experiments will provide important insights into the cellular and circuit mechanisms underlying the rapid anti-depressant effects of ketamine.